We propose to continue the biennial follow-up of cardiovascular disease among 51,529 male health professionals, age 40 to 75 years in 1986, to address a series of new dietary hypotheses related to risk of a coronary heart disease and stroke. We project over 4,000 incident MI, fatal CHD, and stroke cases through the end of the follow-up period. Nested within this cohort, over 18,000 participants provided blood samples in 1994 from which we propose to investigate several biological (plasma and genetic) determinants of disease. We will concentrate on several hypotheses related to nutritional and genetic determinants of cardiovascular disease (CVD). With this exceptional resource of repeated assessments of diet and lifestyle characteristics tied to potential genetic markers of disease, we will prospectively evaluate in relation to coronary heart disease 1) n-6 fatty acids across a wide range of n-3 fatty acid intake from fish and vegetable sources, 2) foods with a high glycemic load, specifically among men with a BMI > 25kg/m^2, 3) protein intake as a replacement for carbohydrate, and 4) putative functional variants and haplotypes in candidate genes thought to be insulin targets. Within this metabolic domain we seek to determine if lifestyle practices such as physical activity or a low glycemic load diet can modify underlying genetic risk. To investigate further the effect of diet on mediators of CHD we will investigate a) the interaction between n- 3 and n-6 fatty acids on inflammatory risk factors for CVD and b) glycemic load on adiponectin and the associated risk of this adipocyte-derived cytokine on risk of MI and fatal CHD. Also, we propose further to examine aims 1-3 with respect to stroke. Finally, within a small exploratory aim, we propose to document basic risk factors for congestive heart failure by utilizing the innovative methods we designed to study coronary heart disease. The ongoing Health Professionals Follow-up Study will provide follow-up of non-CVD endpoints (CA55075) in addition to information on important covariates for the proposed study. Overall, the large size of the prospective cohort, the high follow-up rate, the repeated assessment of dietary and lifestyle information, and the availability of archived bloods provide a unique cost-effective opportunity to test hypotheses related to CVD risk.